The past 5 years have witnessed a dramatic reduction in HIV-associated morbidity and mortality in the developed world, an event that is generally attributed to the advent of highly active antiretroviral therapy. However, the enthusiasm generated by this therapeutic advance has been tempered by widespread reports of potentially deleterious metabolic side effects, including insulin resistance, dyslipidemia, peripheral and/or facial lipoatrophy, and central/visceral fat accumulation, findings reminiscent of syndrome X and commonly referred to as the HIV-associated lipodystrophy syndrome. A major goal of our laboratory has been to not only understand the pathogenesis of HIV-associated metabolic and morphologic abnormalities but also to evaluate novel therapies, using a paradigm based on intensive metabolic ward assessments in which each subject serves as his or her own control. The goal of the present proposal is to evaluate the effects of recombinant human leptin, an adipocyte-derived hormone that appears to have dramatic salutary effects in both murine and human models of lipodystrophy, in HIV-infected patients with lipodystrophy. Two studies will be performed: in the first, we will utilize an open-label design to evaluate the effects of leptin replacement therapy in 12 patients with HIV-lipodystrophy who are also hypoleptinemic, hyperinsulinemic, and hypertriglyceridemic; in the second we will utilize a randomized placebo-control design to extend our investigation of the efficacy of leptin treatment to a group of 40 non-obese HIV-positive patients with diabetes and lipodystrophy. These two studies are designed to test the hypotheses that treatment with leptin will: 1) improve hepatic and peripheral insulin sensitivity and overall carbohydrate metabolism as measured by oral glucose tolerance testing, a euglycemic hyperinsulinemic clamp and stable isotope tracer studies of hepatic glucose production, gluconeogenesis, and glycogen flux; 2) ameliorate abnormalities in lipid metabolism, as measured by plasma lipid and lipoprotein levels and stable isotope studies of whole-body lipolysis and de novo hepatic lipogenesis and cholesterolgenesis; and 3) decrease visceral adiposity, hepatic mass, and intramyocellular lipids, as measured by magnetic resonance imaging and spectroscopy, respectively. To evaluate the effects of leptin on whole-body and regional fat and lean tissue distribution, we will also perform whole-body dual-energy X-ray (DEXA) scanning.